EP1594870B1 - Indolepyridinium substitue utilise comme composes anti-infection - Google Patents

Indolepyridinium substitue utilise comme composes anti-infection Download PDF

Info

Publication number
EP1594870B1
EP1594870B1 EP03811395A EP03811395A EP1594870B1 EP 1594870 B1 EP1594870 B1 EP 1594870B1 EP 03811395 A EP03811395 A EP 03811395A EP 03811395 A EP03811395 A EP 03811395A EP 1594870 B1 EP1594870 B1 EP 1594870B1
Authority
EP
European Patent Office
Prior art keywords
alkyl
mono
nitro
cyano
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP03811395A
Other languages
German (de)
English (en)
Other versions
EP1594870A1 (fr
Inventor
Bart Rudolf Romanie Kesteleyn
Wim Van De Vreken
Natalie Maria Francisca Kindermans
Maxime Francis Jean-Marie Ghislain Canard
Kurt Hertogs
Eva Bettens
Veronique Corine Paul De Vroey
Dirk Edward Désiré JOCHMANS
Piet Tom Bert Paul Wigerinck
Abdellah Tahri
Jing Wang
Dominique Louis Nestor Ghislain Surleraux
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen R&D Ireland ULC
Original Assignee
Tibotec Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tibotec Pharmaceuticals Ltd filed Critical Tibotec Pharmaceuticals Ltd
Priority to EP03811395A priority Critical patent/EP1594870B1/fr
Publication of EP1594870A1 publication Critical patent/EP1594870A1/fr
Application granted granted Critical
Publication of EP1594870B1 publication Critical patent/EP1594870B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to the use of substituted indolepyridinium as anti-infective compounds, and to pharmaceutical compositions and diagnostic kits comprising them.
  • the present invention also concerns combinations of the present substituted indolepyridinium compounds with another anti-retroviral agent. It further relates to their use in assays as reference compounds or as reagents.
  • HIV acquired immunodeficiency syndrome
  • HTLV-III T-lymphocyte virus III
  • LAV lymphadenopathy-associated virus
  • ARV AIDS-related virus
  • HIV human immunodeficiency virus
  • HIV protease inhibitors PIs
  • nucleoside reverse transcriptase inhibitors NRTIs
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • NtRTIs nucleotide reverse transcriptase inhibitors
  • Retroviruses and in particular the HIV virus
  • Resistance of retroviruses, and in particular the HIV virus, against inhibitors is a major cause of therapy failure.
  • half of the patients receiving anti-HIV combination therapy do not respond fully to the treatment, mainly because of resistance of the virus to one or more drugs used.
  • resistant virus is carried over to newly infected individuals, resulting in severely limited therapy options for these drug-naive patients. Therefore, there is a need for new compounds for retrovirus therapy, more particularly for AIDS therapy. This need is particularly acute for compounds that are active not only on wild type HIV virus, but also on the increasingly more common resistant HIV viruses.
  • Boosting plasma levets may also lead to an increased risk af non-comptiance with the prescribed therapy.
  • NRTIs such as zidovudine, didanosine, zaleibatine, stavudine, abacavir and lamivudine
  • NtRTIs such as tenofovir
  • NNRTIs such as nevirapine, delavirdine and efavirenz.
  • the NRTIs and NtRTIs are base analogs that target the active site of HIV reverse transcriptase (RT).
  • RT HIV reverse transcriptase
  • anti-infective compounds that target HIV reverse transcriptase, in particular anti-retroviral compounds that are able to delay the occurrence of resistance and that combat a broad spectrum of mutants of the HIV virus.
  • WO 02/055520 and WO 02/059123 disclose benzoylalkylindolepyridinium compounds as antiviral compounds.
  • Ryabova et al. disclose the synthesis of certain benzoylalkylindolepyridinium compounds ( Russian Chem. Bull. 2001, 50(8), 1449-1456 ) ( Chem. Heterocycl. Compd. (Engl.Translat.)36; 3; 2000; 301 - 306 ; Khim.Geterotsikl.Soedin.; RU; 3; 2000; 362 - 367 ).
  • the invention relates to the inhibition of the replication of HIV virus by substituted indolepyridinium compounds of formula (I) wherein R 1 is cyano, C 1-4 alkylaminocarbonyl or C 1-4 alkyloxycarbonyl; R 2 is hydrogen or C 1-6 alkyl; n is 1 and R 3 is nitro.
  • the compounds of formula (I) are active against wild type HIV virus and also against a variety of mutant HIV viruses including mutant HIV viruses exhibiting resistance against commercially available reverse transcriptase (RT) inhibitors.
  • the compounds of formula (I) are therefore useful as a medicine, and thus also useful in the manufacture of a medicament useful for preventing, treating or combating infection or disease associated with HIV infection.
  • a subgroup of the compounds of formula (I) is deemed novel and consists of those compounds of formula (I) provided they are different from 2,5-dihydro-1-(4-nitrophenyl)-2-oxo-1H-pyrido[3,2-b]indole-3-carbonitrile, and 2,5-dihydro-5-methyl-1-(4-nitrophenyl)-2-oxo-1H-pyrido[3,2-b]indole-3-carbonitrile.
  • the present invention also concerns the compounds of formula (I) having the formula their N -oxides, salts, stereoisomeric forms, racemic mixtures, wherein
  • R 1 is cyano, C 1-4 alkylaminocarbonyl or C 1-4 alkyloxycarbonyl: R 2 is hydrogen or C 1-6 alkyl; n is 1 and R 3 is nitro; provided that the compound is different from 2,5-dihydro-1-(4-nitrophenyl)-2-oxo-1H-pyrido[3,2-b]indole-3-carbonitrile, and 2,5-dihydro-5-methyl-1-(4-nitrophenyl)-2-oxo-1H-pyrido[3,2-b]indole-3-carbonitrile.
  • C 1-4 alkyl as a group or part of a group defmes straight and branched chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 2-methyl-propyl and the like.
  • C 1-6 alkyl as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, the groups defined for C 1-4 alkyl and pentyl, hexyl, 2-methylbutyl, 3-methylpentyl and the like.
  • C 2-6 alkyl as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 2 to 6 carbon atoms such as for example, ethyl, propyl, butyl, 2-methyl-propyl, pentyl, hexyl, 2-methylbutyl, 3-methylpentyl and the like.
  • C 1-10 alkyl as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 10 carbon atoms such as, for example, the groups defined for C 1-6 alkyl and heptyl, octyl, nonyl, decyl and the like.
  • C 2-6 alkenyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond, and having from 2 to 6 carbon atoms, such as, for example, ethenyl, prop-1-enyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, 1-methyl-pent-2-enyl and the like.
  • C 2-10 alkenyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond, and having from 2 to 10 carbon atoms, such as, for example, the groups of C 2-6 alkenyl and hept-1-enyl, hept-2-enyl, hept-3-enyl, oct-1-enyl, oct-2-enyl, oct-3-enyl, non-1-enyl, non-2-enyl, non-3-enyl, non-4-enyl, dec-1-enyl, dec-2-enyl, dec-3-enyl, dec-4-enyl, 1-methyl-pent-2-enyl and the like.
  • C 3-7 cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • halo is generic to fluoro, chloro, bromo or iodo.
  • CAS Chemical Abstracts Nomencalture
  • C 6-14 aryl means an aromatic hydrocarbon ring having from 6 to 14 ring members such as, for example, phenyl, naphthalene, anthracene and phenanthrene.
  • oxadiazolyl may be 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl or 1,2,3-oxadiazolyl; likewise for thiadiazolyl which may be 1,2,4-thiadiazolyl or 1,3,4-thiadiarolyl or 1,2,3-thiadiazolyl; pyrrolyl may be 1H-pyrrolyl or 2H-pyrrolyl.
  • radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable.
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl
  • pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.
  • salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically or physiologically acceptable.
  • salts having a pharmaceutically unacceptable counterion may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound of formula (I). All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable or physiologically tolerable addition salt forms which the compounds of the present invention are able to form can conveniently be prepared using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; hemisulphuric, nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, aspartic, dodecyl-sulphuric, heptanoic, hexanoic, nicotinic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p -toluenesulfonic, cyclamic, salicylic, p -amino-salicylic, pamoic and the like
  • the compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt form by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g . the benzathine, N-methyl, -D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • base addition salt forms can be converted by treatment with an appropriate acid into the free acid form.
  • salts also comprises the hydrates and the solvent addition forms that the compounds of the present invention are able to form. Examples of such forms are e.g . hydrates, alcoholates and the like.
  • N -oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N -oxide.
  • the present compounds may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
  • a 5 membered aromatic heterocycle such as for example an 1,2,4-oxadiazole may be substituted with a hydroxy or a thio group in the 5-position, thus being in equilibrium with its respective tautomeric form as depicted below.
  • stereochemically isomeric forms of compounds of the present invention defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess.
  • the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
  • stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates.
  • the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i. e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e.
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures.
  • enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the diastereomeric racemates of formula (I) can be obtained separately by conventional methods.
  • Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.
  • the present invention is also intended to include all isotopes of atoms occurring on the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • isotopes of carbon include C-13 and C-14.
  • the term "compounds of formula (I)”, or “the present compounds” or similar term is meant to include the compounds of general formula (I), their N-oxides, salts, stereoisomeric forms, racemic mixtures.
  • An interesting subgroup of the compounds of formula (I) or any subgroup thereof are the N -oxides, salts and all the stereoisomeric forms of the compounds of formula (I).
  • n is 1 and the R 3 group on the phenyl ring in the compound of formula (I) is in para-position vis-à-vis the nitrogen atom in the fused pyridine moiety as depicted herein below and hereinafter referred to as compounds of formula (II)
  • a particular group of compounds are those compounds of formula (I) wherein R 1 is cyano, methytoxycarbonyl, methylaminocarbonyl, ethyloxycarbonyl and ethylaminocarbonyl, more in particular wherein R 1 is cyano, ethyloxycarbonyl and ethylaminocarbonyl, even more in particular wherein R 1 is cyano.
  • Another particular group of compounds are those compounds of formula (I) wherein R 2 is hydrogen or C 1-4 alkyl, more in particular wherein R 2 is hydrogen or methyl, even more in particular wherein R 2 is methyl.
  • Yet another particular group of compounds are those compounds of formula (I) wherein R 1 is cyano and R 2 is hydrogen or methyl.
  • a particular group of novel compounds are those compounds of formula (I) wherein R 1 is C 1-4 alkylaminocarbonyl or C 1-4 alkyloxycarbonyl.
  • R 1 is C 1-4 alkylaminocarbonyl or C 1-4 alkyloxycarbonyl and R 2 is hydrogen or methyl.
  • novel compounds are those compounds of formula (I) wherein R 1 is methyloxycarbonyl, methylaminocarbonyl, ethyloxycarbonyl or ethylaminocarbonyl, and R 2 is hydrogen or methyl.
  • Another particular group of novel compounds are those compounds of formula (I) wherein R 2 is C 2-6 alkyl.
  • Another particular group of novel compounds are those compounds of formula (I), wherein when R 1 is cyano then R 2 is different from hydrogen or methyl.
  • Yet another particular group of compounds are those compounds of formula (I) wherein R 2 is hydrogen or C 1-4 alkyl, and the nitro group on the phenyl ring is in the ortho or meta position vis-à-vis the nitrogen atom in the fused pyridine moiety.
  • a suitable group of compounds are those compounds of formula (I) as a salt, wherein the salt is selected from trifluoroacetate, fumarate, chloroacetate, methanesulfonate, oxalate, acetate and citrate.
  • R 1 is hydrogen, cyano, halo, aminocarbonyl, N-hydroxy-methanimidamidyl, Het 1 ; in particular, R 1 is hydrogen, cyano, bromo, tetrazolyl or oxadiazolyl optionally substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, hydroxy, C 1-4 alkoxy, amino, cyano, trifluoromethyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, mono- or di(C 1-4 alkyl)amino, aminoC 1 - 4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, arylC 1-4 alkyl, aminoC 2-6 alkenyl, mono- or di(C 1-4 alkyl)aminoC 2-6 alkenyl, furanyl, thienyl, pyr
  • Suitable compounds are those compounds of formula (II) wherein R 3 is nitro and R 1 is hydrogen, cyano, halo, aminocarbonyl, N -hydroxy-methanimidamidyl, Het 1 . More suitable compounds are those compounds of formula (II) wherein R 3 is nitro, R 2 is C 1-6 alkyl and R 1 is hydrogen, cyano, bromo, tetrazolyl or oxadiazolyl optionally substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, hydroxy, C 1-4 alkoxy, amino, cyano, trifluoromethyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, mono- or di(C 1-4 alkyl)amino, aminoC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, arylC 1-4 alkyl, amino
  • R 2 is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl, wherein said C 1-10 alkyl may be optionally substituted with a substituent selected from the group consisting of cyano, NR 4n R 4b , pyrrolidinyl, piperidinyl, 4-(C 1-4 alkyl)-piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, NCR 4a R 4b )carbonyl, C 1-4 alkyloxycarbonyl, 4-(C 1-4 alkyl)-piperazin-1-ylcarbonyl; in particular R 2 is hydrogen, C 1-6 akyl, C 2-6 alkenyl, cyclopropyl, cyclopentyl, wherein said C 1-6 alkyl may be optionally substituted with a substituent selected from the group consisting of cyano, di(C 1-4 alkyl)
  • Suitable compounds are those compounds of formula (II) wherein R 3 is nitro and R 1 is cyano and R 2 is C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl, wherein said C 1-10 alkyl may be optionally substituted with a substituent selected from the group consisting of cyano, NR 4a R 4b , pyrrolidinyl, piperidinyl, 4-(C 1-4 alkyl)-piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, N(R 4a R 4b )carbonyl, C 1-4 alkyloxycarbonyl, 4-(C 1-4 alkyl)-piperazin-1-ylcarbonyl.
  • R 3 is nitro, cyano, halo, C 1-4 alkyloxy, hydroxycarbonyl, aminocarbonyl, mono- or di(C 1-4 alkyl)methanimidamidyl, N -hydroxy-methanimidamidyl or Het 1 ; more in particular, R 3 is nitro, cyano, halo, C 1-4 alkyloxy, hydroxycarbonyl, aminocarbonyl, mono- or di(C 1-4 alkyl)methanimidamidyl, N- hydroxy-methanimidamidyl, oxadiazolyl, thienyl, thiazolyl, furanyl, isoxazolyl wherein each of said oxadiazolyl, thienyl, thiazolyl, furanyl, isoxazolyl may be substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl,
  • Suitable compounds are those compounds of formula (II) wherein R 1 is cyano and R 3 is nitro, cyano, halo, C 1-4 alkyloxy, hydroxycarbonyl, aminocarbonyl, mono- or di(C 1-4 alkyl)methanimidamidyl, N -hydroxy-methanimidamidyl or Het 1 .
  • More suitable compounds are those compounds of formula (II) wherein R 1 is cyano, R 2 is C 1-6 alkyl and R 3 is nitro, cyano, halo, C 1-4 akloxy, hydroxycarbonyl, aminocarbonyl, mono- or di(C 1-4 alkyl)methanimidamidyl, N -hydroxy-methanimidamidyl, oxadiazolyl, thienyl, thiazolyl, furanyl, isoxazolyl wherein each of said oxadiazolyl, thienyl, thiazolyl, furanyl, isoxazolyl may be substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 2-6 akenyl, C 3-7 cycloalkyl, hydroxy, C 1-4 alkoxy, amino, cyano, trifluoromethyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, mono- or di(C
  • Another embodiment concerns compounds of formula (I) wherein n is 1, R 1 is cyano, halo or oxadiazolyl optionally substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, hydroxy, C 1-4 alkoxy, amino, cyano, trifluoromethyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, mono- or di(C 1-4 alkyl)amino, aminoC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, arylC 1-4 alkyl, aminoC 2-6 alkenyl, mono- or di(C 1-4 alkyl)aminoC 2-6 alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyr
  • Het 1 is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, each of which individually and independently may be optionally substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, hydroxy, C 1-4 alkoxy, halo, amino, cyano, trifluoromethyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, mono- or di(C 1-4 alkyl)amino, aminoC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, arylC 1-4 alkyl, aminoC 2-6
  • Preferred compounds are 1-(4-Nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile; 5-Methyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile; 5-Isobutyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile; 5-Alkyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile; 5-Butyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbon
  • Most preferred compounds are 5-Methyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile; 5-(2-Morpholin-4-yl-ethyl)-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile; 1-(4-Nitro-phenyl)-2-oxo-5-(2-piperidin-1-yl-ethyl)-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile; 1-(4-Nitro-phenyl)-2-oxo-5-(2-pyrrolidin-1-yl-ethyl)-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile; and
  • the compounds of the present invention inhibit the HIV reverse transcriptase and may also inhibit reverse transcriptases having similarity to HIV reverse transcriptase. Such similarity may be determined using programs known in the art including BLAST.
  • the similarity at the amino acid level is at least 25%, interestingly at least 50%, more interestingly at least 75%.
  • the similarity at the amino acid level at the binding pocket, for the compounds of the present invention is at least 75%, in particular at least 90% as compared to HIV reverse transcriptase.
  • Compounds of the present invention have been tested in other lentivirusses besides HIV-1, such as, for example, SIV and HIV-2.
  • the compounds of the present invention have a good selectivity as measured by the ratio between EC 50 and CC 50 as described and exemplified in the antiviral analysis example.
  • the compounds of the present invention have also a favorable specificity. There exists a high dissociation between the activity on lentiviruses versus other retroviridae, such as MLV, and versus non-viral pathogens. For instance, compound 2 had an EC 50 value of more than 32 ⁇ M for Mycobacterium b., Plasmodium f., Trypanosoma b. and Trypanosoma c. whereas the EC 50 value for wild-type HIV was well below 100 nM.
  • the standard of "sensitivity” or alternatively “resistance” of a HIV reverse transcriptase enzyme to a drug is set by the commercially available HIV reverse transcriptase inhibitors.
  • Existing commercial HIV reverse transcriptase inhibitors including efavirenz, nevirapine and delavirdine may loose effectivity over time against a population of HIV virus in a patient. The reason being that under pressure of the presence of a particular HIV reverse transcriptase inhibitor, the existing population of HIV virus, usually mainly wild type HIV reverse transcriptase enzyme, mutates into different mutants which are far less sensitive to that same HIV reverse transcriptase inhibitor. If this phenomenon occurs, one talks about resistant mutants.
  • One way of expressing the resistance of a mutant to a particular HIV reverse transcriptase inhibitor is making the ratio between the EC 50 of said HIV reverse transcriptase inhibitor against mutant HIV reverse transcriptase over EC 50 of said HIV reverse transcriptase inhibitor against wild type HIV reverse transcriptase. Said ratio is also called fold change in resistance (FR).
  • the EC 50 value represents the amount of the compound required to protect 50% of the cells from the cytopathogenic effect of the virus.
  • Clinically relevant mutants of the HIV reverse transcriptase enzyme may be characterized by a mutation at codon position 100, 103 and 181.
  • a codon position means a position of an amino acid in a protein sequence. Mutations at positions 100, 103 and 181 relate to non-nucleoside RT inhibitors ( D'Aquila et al. Topics in HIV medicine, 2002, 10, 11-15 ). Examples of such clinical relevant mutant HIV reverse transcriptases are listed in Table 1. Table I List of mutations present in reverse transcriptase of the HIV strains used.
  • An interesting group of compounds are those compounds of formula (I) having a fold resistance ranging between 0.01 and 100 against at least one mutant HIV reverse transcriptase, suitably ranging between 0.1 and 100, more suitably ranging between 0.1 and 50, and even more suitably ranging between 0.1 and 30.
  • the compounds of formula (I) showing a fold resistance against at least one mutant HIV reverse transcriptase ranging between 0.1 and 20 are particularly interesting.
  • An interesting group of compounds are those compounds of formula (I) having a fold resistance, determined according to the methods herein described, in the range of 0.01 to 100 against HIV species having at least one mutation in the amino acid sequence of HIV reverse transcriptase as compared to the wild type sequence (genbank accession e.g. M38432, K03455, gi 327742) at a position selected from 100, 103 and 181; in particular at least two mutations selected from the positions 100, 103 and 181.
  • Even more interesting are those compounds within said interesting group of compounds having a fold resistance in the range of 0.1 to 100, in particular in the range 0.1 to 50, more in particular in the range 0.1 to 30.
  • Most interesting are those compounds within said interesting group of compounds having a fold resistance in the range of 0.1 and 20, especially ranging between 0.1 and 10.
  • the compounds of the present invention show a fold resistance in the ranges mentioned just above against at least one clinically relevant mutant HIV reverse transcriptases.
  • a particular group of compounds are those compounds of formula (I) having an IC 50 of 1 ⁇ M or lower, suitably an IC 50 of 100 nM or lower vis-à-vis the wild type virus upon in vitro screening according to the methods described herein.
  • the ability of the present compounds to inhibit HIV-1, HIV-2, SIV and HIV viruses with reverse transcriptase (RT) enzymes having mutated under pressure of the currently known RT inhibitors indicate that the present compounds bind differently to the RT enzyme when compared to the known NNRTIs and NRTIs.
  • RT reverse transcriptase
  • a study with more than 8000 viruses showed that the calculated correlation coefficient between the present compound 2 and known NRTIs, such as for example 3TC, abacavir, AZT, D4T, DDC, DDI, was in all cases lower than 0.28 with an exception of 3TC where the correlation coefficient was about 0.63.
  • the correlation coefficient between the present compound 2 and known NNRTIs such as for example capravirine, delavirdine, nevirapine and efavirenz was in all cases about 0.13 or lower.
  • the compounds of the present invention show antiretroviral properties, in particular against Human Immunodeficiency Virus (HIV), which is the aetiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans.
  • HIV Human Immunodeficiency Virus
  • the HIV virus preferentially infects CD4 receptor containing cells such as human T4 cells and destroys them or changes their normal function, particularly the coordination of the immune system.
  • an infected patient has an ever-decreasing number of T4 cells, which moreover behave abnormally.
  • the immunological defence system is unable to combat infections and/or neoplasms and the HIV infected subject usually dies by opportunistic infections such as pneumonia, or by cancers.
  • HIV infection Other diseases associated with HIV infection include thrombocytopaenia, Kaposi's sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as, progressive dysarthria, ataxia and disorientation. HIV infection further has also been associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC). The HIV virus also infects CD8-receptor containing cells. Other target cells for HIV virus include microglia, dendritic cells, B-cells and macrophages.
  • the compounds of the present invention or any subgroup thereof may be used as medicines against above-mentioned diseases or in the prophylaxis thereof.
  • Said use as a medicine or method of treatment comprises the systemic administration to HIV-infected subjects of an amount effective to combat the conditions associated with HIV.
  • the present invention concerns the use of a compound of formula (I) or any subgroup thereof in the manufacture of a medicament useful for preventing, treating or combating infection or disease associated with HIV infection.
  • the present invention concerns the use of a compound of formula (I) or any subgroup thereof in the manufacture of a medicament useful for inhibiting replication of a HIV virus, in particular a HIV virus having a mutant HIV reverse transcriptase, more in particular a multi-drug resistant mutant HIV reverse transcriptase.
  • the present invention relates to the use of a compound of formula (I) or any subgroup thereof in the manufacture of a medicament useful for preventing, treating or combating a disease associated with HIV viral infection wherein the reverse transcriptase of the HIV virus is mutant, in particular a multi-drug resistant mutant HIV reverse transcriptase.
  • the compounds of formula (I) or any subgroup thereof are also useful in a method for preventing, treating or combating infection or disease associated with HIV infection in a mammal, comprising administering to said mammal an effective amount of a compound of formula (I) or any subgroup thereof.
  • the compounds of formula (I) or any subgroup thereof are useful in a method for preventing, treating or combating infection or disease associated with infection of a mammal with a mutant HIV virus, comprising administering to said mammal an effective amount of a compound of formula (I) or any subgroup thereof.
  • the compounds of formula (I) or any subgroup thereof are useful in a method for preventing, treating or combating infection or disease associated with infection of a mammal with a multi drug-resistant HIV virus, comprising administering to said mammal an effective amount of a compound of formula (I) or any subgroup thereof.
  • the compounds of formula (I) or any subgroup thereof are useful in a method for inhibiting replication of a HIV virus, in particular a HIV virus having a mutant HIV reverse transcriptase, more in particular a multi-drug resistant mutant HIV reverse transcriptase, comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) or any subgroup thereof.
  • a mammal as mentioned in the present methods is a human being.
  • the compounds of the present invention may also find use in inhibiting ex vivo samples containing HIV or expected to be exposed to HIV. Hence, the present compounds may be used to inhibit HIV present in a body fluid sample that contains or is suspected to contain or be exposed to HIV.
  • reaction products may be isolated from the medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography.
  • synthesis of compounds (a-6) and (a-7) conveniently starts from 1-C 1-6 alkylcarbonyl-3-hydroxyindole (a-1) .
  • the nitroaniline is para-nitroaniline.
  • Intermediate (a-2) can then be deacylated with a base, such as for example triethylamine, sodiumhydroxide, sodiumacetate, potassiumacetate or potassiumcarbonate and the like, in a suitable solvent, such as for example methanol or ethanol, and at elevated temperature, yielding intermediate (a-3) .
  • a base such as for example triethylamine, sodiumhydroxide, sodiumacetate, potassiumacetate or potassiumcarbonate and the like
  • a suitable solvent such as for example methanol or ethanol
  • intermediate (a-5) Subsequent intramolecular cyclisation of intermediate (a-5) at elevated temperature and in a solvent like ethyleneglycol, dioxane, N,N-dimethylformamide, dimethylsulfoxide, glyme, diglyme and the like, yields compound (a-6) which may be transformed into a compound of formula (a-7) using an N-alkylation reaction with an intermediate of formula R 2 -X wherein X is a leaving group.
  • leaving groups include sulfonates such as tosylate, mesylate; acetates; halogens such bromide, iodide, chloride and fluoride.
  • transformations from the compounds of formula (a-6) and (a-7) may be performed using art-known transformation techniques.
  • the compounds of formula (a-6) or (a-7) wherein R 3 is nitro may be reduced to R 3 being amino, and may then be further derivatized.
  • Further examples of transformation reactions are given in example schemes A2 through A15 in the experimental part.
  • the order of the mentioned steps in said process scheme A may be different.
  • the formylation may be performed prior to deacylation.
  • the intermediate (b-1) may be reacted with a reagent of formula (i) in a suitable solvent such as for example toluene, acetic acid, an alcohol and the like, in the presence of a catalyst such as for example p-toluenesulfonic acid to yield an intermediate of formula (b-2). Elevated temperatures and stirring may enhance the reaction. Said intermediate (b-2) may then be reacted with chloroacetyl chloride or a functional derivative thereof, suitable at elevated temperature, to yield an intermediate of formula (b-3).
  • a suitable solvent such as for example toluene, acetic acid, an alcohol and the like
  • a catalyst such as for example p-toluenesulfonic acid
  • Said intermediate of formula (b-3) may be deprotected using a suitable base such as trietylamine, sodiumacetate, potassium acetate, sodiumhydroxide, potassiumhydroxide, potassiumcarbonate and the like, in a solvent like methanol or ethanol. Stirring and heating may enhance the reaction.
  • the thus formed intermediate of formula (b-4) may be cyclised by first using potassiumcyanide or tetrabutylammoniumcyanide, and subsequently submitting the intermediate to a Vilsmeier formylation using POCl 3 in N,N-dimethylformamide to form compound (b-5) which belongs to the class of compounds of formula (I).
  • Said compound (b-5) may further be transformed into other compounds of formula (I) using art-known transformation reactions. Of which several are described in the exemplary scheme in the experimental part of the description. For example where R 3 is Br, Br may be transformed into a Heterocyclic ring using Heterocyclic borates and palladium.
  • the intermediate (c-1) may be reacted with a reagent of formula (i) in a suitable solvent such as for example toluene, acetic acid, an alcohol and the like, in the presence of a catalyst such as for example p-toluenesulfonic acid to yield an intermediate of formula (c-2). Elevated temperatures and stirring may enhance the reaction.
  • Said intermediate (c-2) may then be reacted with acetic anhydride in the presence of a catalyst such as for example pyridine or dimethylaminopyridine or the like, suitable at elevated temperature, to yield an intermediate of formula (c-3).
  • intermediate (c-3) may be reacted using a Vilsmeier reaction with POCl 3 in N,N-dimethylformamide to form intermediate (c-4) which in turn can be further cyclised to compound (c-5) in an aqueous acidic environment.
  • Said compound (c-5), belonging to the class of compounds of formula (I), may further be transformed into other compounds of formula (I) using art-known transformation reactions.
  • Art-known transformation reactions Of which several are described in the exemplary scheme in the experimental part of the description.
  • R 3 being C 1 - 6 alkyloxycarbonyl may be transformed to the equivalent carboxylic acid or amide.
  • R 3 being cyano may be transformed to a heterocycle such as a tetrazolyl, oxadiazolyl, thiazolyl etc.
  • An intermediate of formula (d-1) can be reacted with a C 1-6 alkyliodide or C 1-6 alkyl-sulfate in the presence of a base such as for example potassium carbonate, potassiumhydroxide, sodiumhydroxide and the like, in a reaction-inert solvent such as for example N,N-dimethylformamide, acetonitrile, acetone, ethanol, water and the like. Stirring may enhance the reaction rate.
  • the thus formed intermediate of formula (d-2) can then be further reacted with hydroxylamine in a solvent like water, ethanol or a mixture thereof and in the presence of a base like sodiumacetate, potassium acetate, potassium carbonate, sodiumacetate and the like, to form an intermediate of formula (d-3).
  • an intermediate of formula (d-4) Upon heating and bringing the intermediate of formula (d-3) in an acidic aqueous environment, an intermediate of formula (d-4) is formed. Said intermediate can then be subjected to an intramolecular cyclisation in the presence of POCl 3 in N,N-dimethylformamide. Cooling the reaction mixture may be advantageous.
  • the thus formed intermediate of formula (d-5) can be treated with Zinc in an acidic aqueous environment such as HCl to form an intermediate of formula (d-6).
  • the N-oxide can be prepared using metachloroperbenzoic acid, waterperoxide, tert-butylhydroperoxide and the like, or a functional equivalent thereof in a solvent such as, for example, dichloromethane, chloroform, an alcohol, toluene or the like, and employing elevated temperatures.
  • Said N-oxide of formula (d-7) can be further reacted, suitably at elevated temperature, with acetic anhydride to form the intermediate of formula (d-8).
  • a boronic acid of formula (ii) can be used to prepare the compounds of formula (I) equivalent to the formula (d-9).
  • Said reaction step involves the use of copper(II) acetate or an equivalent thereof in a solvent such as for example N,N-dimethylformamide, dichloromethane, toluene, an alcohol, chloroform and the like.
  • a quencher like pyridine may be added to the reaction mixture. Elevating the temperature may enhance the reaction.
  • the compounds of formula (I) wherein R 2 is hydrogen can be transformed into compounds of formula (I) wherein R 2 is different from hydrogen.
  • reagents like R 2 -Cl wherein Cl is a leaving group can be used in the presence of a base such as sodium hydride or potassium carbonate, potassium hydroxide, sodiumhydroxide and the like.
  • a base such as sodium hydride or potassium carbonate, potassium hydroxide, sodiumhydroxide and the like.
  • Other suitable leaving groups may also be employed such as for example sulfonates such as tosylate, mesylate; acetates; halogens such bromide, iodide, chloride and fluoride.
  • the reaction procedure can be used for introducing for instance
  • the compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form.
  • Said N -oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide.
  • Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide;
  • appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g.
  • 3-chloro-benzenecarboperoxoic acid peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert -butyl hydroperoxide.
  • Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
  • a basic nitrogen occurring in the present compounds can be quaternized with any agent known to those of ordinary skill in the art including, for instance, lower alkyl halides, dialkyl sulfates, long chain halides and aralkyl halides according to art-known procedures.
  • the present compounds can thus be used in animals, preferably in mammals, and in particular in humans as pharmaceuticals per se, in mixtures with one another or in the form of pharmaceutical preparations.
  • the present invention relates to pharmaceutical preparations that as active constituents contain an effective dose of at least one of the compounds of formula (I) in addition to customary pharmaceutically innocuous excipients and auxiliaries.
  • the pharmaceutical preparations normally contain 0.1 to 90% by weight of a compound of formula (I).
  • the pharmaceutical preparations can be prepared in a manner known per se to one of skill in the art. For this purpose, at least one of a compound of formula (I), together with one or more solid or liquid pharmaceutical excipients and/or auxiliaries and, if desired, in combination with other pharmaceutical active compounds, are brought into a suitable administration form or dosage form which can then be used as a pharmaceutical in human medicine or veterinary medicine.
  • compositions which contain a compound according to the invention can be administered orally, parenterally, e.g., intravenously, rectally, by inhalation, or topically, the preferred administration being dependent on the individual case, e.g., the particular course of the disorder to be treated. Oral administration is preferred.
  • auxiliaries that are suitable for the desired pharmaceutical formulation.
  • Beside solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound carriers, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, agents for achieving a depot effect, buffer substances or colorants are also useful.
  • the combination of an antiretroviral compound and a compound of the present invention can be used as a medicine.
  • the present invention also relates to a product containing (a) a compound of the present invention, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in treatment of retroviral infections such as HIV infection, in particular, in the treatment of infections with multi-drug resistant retroviruses.
  • the compounds of this invention may be co-administered in combination with for instance, binding inhibitors, such as, for example, dextran sulfate, suramine, polyanions, soluble CD4, PRO-542, BMS-806; fusion inhibitors, such as, for example, T20, Tri249, RPR 103611, YK-FH312, IC 9564, 5-helix, D-peptide ADS-J1; co-receptor binding inhibitors, such as, for example, AMD 3100, AMD-3465, AMD7049, AMD3451 (Bicyclams), TAK 779, T-22, ALX40-4C; SHC-C (SCH351125), SHC-D, PRO-140, RPR103611; RT inhibitors, such as, for example, foscarnet and prodrugs; nucleoside RTIs,
  • binding inhibitors such as, for example, dextran sulfate, suramine, polyanions, soluble CD4, PRO-542, BMS-806
  • the combination may provide a synergistic effect, whereby viral infectivity and its associated symptoms may be prevented, substantially reduced, or eliminated completely.
  • the compounds of the present invention may also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, methionine enkephalin, interferon alpha, and naltrexone) with antibiotics (e.g., pentamidine isothiorate) cytokines (e.g. Th2), modulators of cytokines, chemokines or modulators of chemokines, chemokine receptors (e.g. CCR5, CXCR4), modulators chemokine receptors, or hormones (e.g. growth hormone) to ameliorate, combat, or eliminate HIV infection and its symptoms.
  • immunomodulators e.g., bropirimine, anti-human alpha interferon antibody, IL-2, methionine enkephalin, interferon alpha, and naltrexone
  • antibiotics e.g., pentamidine isothiorate
  • cytokines e.g. Th
  • the compounds of the present invention may also be administered in combination with modulators of the metabolization following application of the drug to an individual.
  • modulators include compounds that interfere with the metabolization at cytochromes, such as cytochrome P450. It is known that several isoenzymes exist of cytochrome P450, one of which is cytochrome P450 3A4.
  • Ritonavir is an example of a modulator of metabolization via cytochrome P450.
  • Such combination therapy in different formulations may be administered simultaneously, sequentially or independently of each other. Alternatively, such combination may be administered as a single formulation, whereby the active ingredients are released from the formulation simultaneously or separately.
  • Such modulator may be administered at the same or different ratio as the compound of the present invention.
  • the weight ratio of such modulator vis-à-vis the compound of the present invention is 1:1 or lower, more preferable the ratio is 1:3 or lower, suitably the ratio is 1:10 or lower, more suitably the ratio is 1:30 or lower.
  • compounds of the present invention are mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions.
  • suitable inert carriers are gum ilute, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch. In this case the preparation can be carried out both as dry and as moist granules.
  • Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.
  • Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof.
  • Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms.
  • the active compounds For subcutaneous or intravenous administration, the active compounds, if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries, are brought into solution, suspension, or emulsion.
  • the compounds of formula (I) can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations.
  • Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned.
  • Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of formula (I) or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents.
  • a pharmaceutically acceptable solvent such as ethanol or water, or a mixture of such solvents.
  • the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
  • Such a preparation customarily contains the active compound in a concentration from approximately 0.1 to 50%, in particular from approximately 0.3 to 3% by weight.
  • cyclodextrins are ⁇ -, ⁇ - or ⁇ -cyclodextrins (CDs) or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C 1-6 alkyl, particularly methyl, ethyl or isopropyl, e.g.
  • ⁇ -CD randomly methylated ⁇ -CD
  • hydroxyC 1-6 alkyl particularly hydroxyethyl, hydroxypropyl or hydroxybutyl
  • carboxyC 1-6 alkyl particularly carboxymethyl or carboxyethyl
  • C 1-6 alkyl-carbonyl particularly acetyl
  • C 1-6 alkylcarbonyloxyC 1-6 alkyl particularly 2-acetyloxypropyl.
  • complexants and/or solubilizers are ⁇ -CD, randomly methylated ⁇ -CD, 2,6-dimethyl- ⁇ -CD, 2-hydroxyethyl- ⁇ -CD, 2-hydroxyethyl- ⁇ -CD, 2-hydroxypropyl- ⁇ -CD and (2-carboxymethoxy)propyl- ⁇ -CD, and in particular 2-hydroxypropyl- ⁇ -CD (2-HP- ⁇ -CD).
  • mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxyethyl.
  • formulations described therein are with antifungal active ingredients, they are equally interesting for formulating the compounds of the present invention.
  • the formulations described therein are particularly suitable for oral administration and comprise an antifungal as active ingredient, a sufficient amount of a cyclodextrin or a derivative thereof as a solubilizer, an aqueous acidic medium as bulk liquid carrier and an alcoholic co-solvent that greatly simplifies the preparation of the composition.
  • Said formulations may also be rendered more palatable by adding pharmaceutically acceptable sweeteners and/or flavours.
  • the present compounds may be formulated in a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of particles consisting of a solid dispersion comprising (a) a compound of formula (I), and (b) one or more pharmaceutically acceptable water-soluble polymers.
  • a solid dispersion defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components.
  • a solid solution When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution”.
  • Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered.
  • a solid dispersion also comprises dispersions which are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase.
  • the water-soluble polymer in the particles is conveniently a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2 % aqueous solution at 20°C solution.
  • Preferred water-soluble polymers are hydroxypropyl methylcelluloses or HPMC.
  • HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water soluble.
  • Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule.
  • Hydroxy-propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule.
  • the particles as defined hereinabove can be prepared by first preparing a solid dispersion of the components, and then optionally grinding or milling that dispersion.
  • Various techniques exist for preparing solid dispersions including melt-extrusion, spray-drying and solution-evaporation, melt-extrusion being preferred.
  • the present compounds may further be convenient to formulate the present compounds in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm.
  • Useful surface modifiers are believed to include those that physically adhere to the surface of the antiretroviral agent but do not chemically bond to the antiretroviral agent.
  • Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include iluted c and anionic surfactants.
  • Yet another interesting way of formulating the present compounds involves a pharmaceutical composition whereby the present compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bioavailability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.
  • Said beads comprise (a) a central, rounded or spherical core, (b) a coating film of a hydrophilic polymer and an antiretroviral agent and (c) a seal-coating polymer layer.
  • Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness.
  • examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.
  • the route of administration may depend on the condition of the subject, co-medication and the like.
  • kits or containers comprising a compound of formula (I) in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.
  • This aspect of the invention may find its use in pharmaceutical research programs.
  • the compounds of the present invention can be used in phenotypic resistance monitoring assays, such as known recombinant assays, in the clinical management of resistance developing diseases such as HIV.
  • a particularly useful resistance monitoring system is a recombinant assay known as the Antivirogram ®
  • the Antivirogram ® is a highly automated, high throughput, second generation, recombinant assay that can measure susceptibility, especially viral susceptibility, to the compounds of the present invention. ( Hertogs K et al. Antimicrob Agents Chemother, 1998; 42(2):269-276 , incorporated by reference).
  • the compounds of the present invention may comprise chemically reactive moieties capable of forming covalent bonds to localized sites such that said compound have increased tissue retention and half-lives.
  • chemically reactive group refers to chemical groups capable of forming a covalent bond. Reactive groups will generally be stable in an aqueous environment and will usually be carboxy, phosphoryl, or convenient acyl group, either as an ester or a mixed anhydride, or an imidate, or a maleimidate thereby capable of forming a covalent bond with functionalities such as an amino group, a hydroxy or a thiol at the target site on for example blood components such as albumine.
  • the compounds of the present invention may be linked to maleimide or derivatives thereof to form conjugates.
  • the dose of the present compounds or of the physiologically tolerable salt(s) thereof to be administered depends on the individual case and, as customary, is to be adapted to the conditions of the individual case for an optimum effect. Thus it depends, of course, on the frequency of administration and on the potency and duration of action of the compounds employed in each case for therapy or prophylaxis, but also on the nature and severity of the infection and symptoms, and on the sex, age, weight co-medication and individual responsiveness of the human or animal to be treated and on whether the therapy is acute or prophylactic.
  • the daily dose of a compound of formula (I) in the case of administration to a patient approximately 75 kg in weight is 1 mg to 3 g, preferably 3 mg to 1 g, more preferably, 5 mg to 0.5 g.
  • the dose can be administered in the form of an individual dose, or divided into several, e.g. two, three, or four, individual doses.
  • DMF N,N-dimethylformamide
  • first reaction vessel The contents of first reaction vessel were then added dropwise to the stirred POCl 3 -DMF complex in the second reaction vessel while the temperature was kept ⁇ 10°C .
  • Tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv., 0.026 mmol, 24 mg) was added to a solution of tri(t-butyl)phosphine in toluene (0.24 equiv., 0.0635 mmol, 0.4 M, 159 ⁇ l) in a sealed tube. Dry THF (3 ml) was added and the reaction mixture was stirred under nitrogen at room temperature for 10 minutes.
  • Table 2 Comp. No. Synthesis scheme R 2 Salt form 1 A1 H 2 A1 CH 3 3 A9 4 A7 5 A7 6 A7 benzyl 7 A7 8 A7 1-butyl 9 A7 ethyl 10 A7 cyclopentyl 11 A7 12 13 A7 14 A7 chlorohydrate 15 A7 oxalate 16 A7 methanesulfonate 17 A7 18 A7 19 A9 20 A9 21 A8 22 A8 23 A8 24 A8 25 A8 26 A8 27 A7 28 A8 29 A8 30 A9 31 A7 32 A8 33 A7 34 A7 35 A7 36 A7 125 A9 Table 3 Comp.
  • a time of addition experiment was performed to determine the mechanism of action of the compounds of the present invention.
  • compounds are added to cells that were infected with HIV, at time zero (Zero hours).
  • the compounds are subsequently added at different points in time.
  • the time point until which a compound can be added to prevent virus replication, provides an indication of the mechanism of action of the compound.
  • MT4 cells were infected with HIV-1 strain LAI at time zero.
  • compounds were subsequently added at the points in time indicated in the X-axis of Figure 1 (in hours).
  • the compounds were added at the following end concentrations during incubation: DS5000, 1 ⁇ M; efavirenz (EFV), 1 ⁇ M; saquinavir (SQV), 1 ⁇ M; Reference 1, 10 ⁇ M (Reference 1 is an integrase inhibitor selected from WO 99/62520 and is present in CAS database: 251963-93-6); Compound 2, 50 ⁇ M; Control: normalized virus production.
  • the virus production was determined using p24 monitoring using a kit according to the manufacturers instructions (p24 ELISA kit, catalog reference NEK-050, Perkin Elmer).
  • Compound 2 delayed virus production using a mechanism related to reverse transcriptase.
  • the assay was run using kit TRK 1022 (Amersham Life Sciences) according to the manufacturer's instructions with slight modifications. Compounds were diluted in steps of 1/4 in 100% DMSO and subsequently transferred to Medium A (1/50 dilution; medium A: RPMI 1640 + 10% FetalClone II + Gentamycin 20 mg/L). 25 ⁇ l of compound (in 2% DMSO in Medium A) or 25 ⁇ l of 2% DMSO in medium A was added to wells.
  • Compound 2 inhibits HIV reverse transcriptase in vitro and consequently does not need conversion to an active metabolite in order to inhibit reverse transcriptase.
  • the present experiment provides insight into the hepatic first pass metabolization of compounds.
  • the incubations 30 or 120 minutes at 37°C, were initiated by adding 10 ⁇ l of a solution of nicontinamide adenine dinucleotide phosphate (1,25 mg/ml) in homogenisation buffer. After a preincubation during 5 minutes at 37 °C, the tubes were continuously shaken at 100 oscillations /minute in a water bath. The reactions were terminated by addition of an equal volume of DMSO. Blank incubations containing boiled microsomal fractions were incubated under the same conditions as the drug incubations. The degree of metabolism was determined by direct measurement of the residual parent compound in the reaction mixture using LC-MS.
  • the residual anti-HIV activity in the reaction mixture was detected using a colorimetric anti-HIV assay as described in Pauwels et al. J. Virol. Methods 1988 (20) 309-321 .
  • the residual activity is defined as the percent difference in EC 50 between the drug incubations and the blank incubations.
  • the compounds of the present invention were examined for anti-viral activity in a cellular assay.
  • the assay demonstrated that these compounds exhibit potent anti-HIV activity against a wild type laboratory HIV strain (HIV-1 strain LAI).
  • the cellular assay was performed according to the following procedure.
  • HIV- or mock-infected MT4 cells were incubated for five days in the presence of various concentrations of the inhibitor. At the end of the incubation period, the replicating virus in the control cultures has killed all HIV-infected cells in the absence of any inhibitor. Cell viability was determined by measuring the concentration of MTT, a yellow, water soluble tetrazolium dye that is converted to a purple, water insoluble formazan in the mitochondria of living cells only. Upon solubilization of the resulting formazan crystals with isopropanol, the absorbance of the solution was monitored at 540 nm. The values correlate directly to the number of living cells remaining in the culture at the completion of the five day incubation.
  • MTT a yellow, water soluble tetrazolium dye that is converted to a purple, water insoluble formazan in the mitochondria of living cells only.
  • the inhibitory activity of the compound was monitored on the virus-infected cells and was expressed as EC 50 and EC 90 . These values represent the amount of the compound required to protect 50% and 90%, respectively, of the cells from the cytopathogenic effect of the virus.
  • the toxicity of the compound was measured on the mock infected cells and was expressed as CC 50 , which represents the concentration of compound required to inhibit the growth of the cells by 50%.
  • the selectivity index (SI) ratio CC 50 /EC 50
  • SI selectivity index
  • the present compounds are effective in inhibiting a broad range of mutant strains: Row A: pEC 50 value towards mutant A, Row B: pEC 50 towards mutant B , Row C: pEC 50 towards mutant C, Row D: pEC 50 towards mutant D, Row E: pEC 50 towards mutant E, Row F: pEC 50 towards mutant F, Row G: pEC 50 towards mutant G, Row H: pEC 50 towards mutant G, Row H: pEC 50 towards mutant H, Row I: pEC 50 towards mutant I, Row J: pEC 50 towards mutant J, Row K: pEC 50 towards mutant K, Row HIV-2: pEC 50 towards mutant HIV-2, Row SIV (simian immunodeficiency virus): pEC 50 towards mutant SIV.
  • 2-(dimethylamino)-4,5-dihydro-5-methyl-1-(4-nitrophenyl)-4-(2-oxopropyl)-1H-pyrido[3,2-b]indole-3-carbonitrile as mentioned in WO 02/055520 has a pEC 50 for wild type HIV virus of 5.5 indicating an increase in potency for the compounds of the present invention ranging between about 1 and 2 log units.
  • the other compounds exemplified in the present application have also been tested for their antiviral activity. With respect to their ability to inhibit the wild-type HIV-LAI strain, the compound numbers 5, 7, 8,9,11,12,13,14,15,16,17,18,21, 23,25,26, 27, 28, 29, 32, 35, 43, 67, 68, 71 and 72 had an EC 50 value of lower than 1 ⁇ M.
  • Active ingredient, in casu a compound of formula (I), can be dissolved in organic solvent such as ethanol, methanol or methylene chloride, preferably, a mixture of ethanol and methylene chloride.
  • organic solvent such as ethanol, methanol or methylene chloride, preferably, a mixture of ethanol and methylene chloride.
  • Polymers such as polyvinylpyrrolidone copolymer with vinyl acetate (PVP-VA) or hydroxypropylmethylcellulose (HPMC), typically 5 mPa.s, can be dissolved in organic solvents such as ethanol, methanol methylene chloride.
  • the polymer can be dissolved in ethanol.
  • the polymer and compound solutions can be mixed and subsequently spray dried.
  • the ratio of compound/polymer can be selected from 1/1 to 1/6. Intermediate ranges can be 1/1.5 and 1/3. A suitable ratio can be 1/6.
  • the spray-dried powder, a solid dispersion can subsequently be filled in capsules for administration
  • a mixture of 100 g of active ingredient, in casu a compound of formula (I), 570 g lactose and 200 g starch can be mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water.
  • the wet powder mixture can be sieved, dried and sieved again.
  • 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil The whole can be mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient.

Abstract

La présente invention concerne les composés représentés par la formule (I) (1) (R3)n P(I) N O R1 R2 les N-oxydes, sels, formes stéréo-isomères, mélanges racémiques, promédicaments, esters et métabolites de ceux-ci. Dans cette formule n est 1, 2 ou 3; R1 est H, CN, halo, aminoC(=O), C(=O)OH, C1-4-alkyloxyC(=O), C1-4alkylC(= O), mono- ou di(C1-4alkyl)aminoC(=O), arylaminoC(=O), N-(aryl)-N-(C1-4alkyl)aminoC(=O), méthanimidamidyle, N-hydroxy-méthanimidamidyle, mono- ou di(C1-4alkyl)méthanimidamidyle, Het1 ou Het2; R2 est H, C1-10alkyle, C2-10allkényle, C3-7cycloalkyle, ces groupes C1-10alkyle,C2-10alkényle et C3-7cycloalkyle pouvant éventuellement être substitués; R3 est nitro, cyano, amino, halo, hydroxy,C1-4alkyloxy, hydroxyC(=O), aminoC(=O), C1-4alkyloxyC(=O), mono- ou di(C1-4-alkyl)aminoC(=O), C1-4alkylC(=O), méthanimidamidyle, mono- ou di(C1-4alkyl)méthanimidamidyle, N-hydroxy méthanimidamidyle ou Het1; ces composés sont à usage médicinal. Cette invention concerne aussi un nouveau sous groupe de composés représentés par la formule (I) et des compositions comprenant les composés de la formule (I).

Claims (27)

  1. Composé de formule (I)
    Figure imgb0153
     son N-oxyde, son sel, sa forme stéréoisomère, son mélange racémique,
    dans laquelle
    n est 1, 2 ou 3 ;
    R1 est hydrogène, cyano, halogéno, aminocarbonyle, hydroxycarbonyle, C1-4alkyloxycarbonyle, C1- 4alkylcarbonyle, mono- ou di(C1- 4alkyl)aminocarbonyle, arylaminocarbonyle, N- (aryl)-N-(C1-4alkyl)aminocarbonyle, méthanimidamidyle, N-hydroxy- méthanimidamidyle, mono- ou di(C1- 4alkyl)méthanimidamidyle, Het1 ou Het2 ;
    R2 est hydrogène, C1-10alkyle, C2-10alcényle, C3- 7cycloalkyle, où lesdits C1-10alkyle, C2- 10alcényle et C3-7cycloalkyle, chacun individuellement et indépendamment, peuvent être éventuellement substitués par un substituant choisi dans le groupe constitué de cyano, NR4aR4b, pyrrolidinyle, pipéridinyle, homopipéridinyle, pipérazinyle, 4-(C1-4alkyl)- pipérazinyle, morpholinyle, thiomorpholinyle, 1-oxothiomorpholinyle, 1,1-dioxo- thiomorpholinyle, aryle, furanyle, thiényle, pyrrolyle, oxazolyle, thiazolyle, imidazolyle, isoxazolyle, isothiazolyle, pyrazolyle, oxadiazolyle, thiadiazolyle, triazolyle, tétrazolyle, pyridyle, pyrimidinyle, pyrazinyle, pyridazinyle, triazinyle, hydroxy-carbonyle, C1- 4alkylcarbonyle, N(R4aR4b)carbonyle, C1- 4alkyloxycarbonyle, pyrrolidin-1-ylcarbonyle, pipéridin-1-ylcarbonyle, homopipéridin-1- ylcarbonyle, pipérazin-1-ylcarbonyle, 4-(C1- 4alkyl)-pipérazin-1-ylcarbonyle, morpholin-1- yl-carbonyle, thiomorpholin-1-ylcarbonyle, 1- oxothiomorpholin-1-ylcarbonyle et 1,1-dioxo- thiomorpholin-1-ylcarbonyle ;
    R3 est nitro, cyano, amino, halogéno, hydroxy, C1- 4alkyloxy, hydroxycarbonyle, aminocarbonyle, C1-4alkyloxycarbonyle, mono- ou di(C1- 4alkyl)aminocarbonyle, C1-4alkylcarbonyle, méthanimidamidyle, mono- ou di(C1- 4alkyl)méthanimidamidyle, N-hydroxy- méthanimidamidyle ou Het1 ;
    R4a est hydrogène, C1-4alkyle ou C1-4alkyle substitué par un substituant choisi dans le groupe constitué d'amino, mono- ou di(C1- 4alkyl)amino, pyrrolidinyle, pipéridinyle, homopipéridinyle, pipérazinyle, 4-(C1-4alkyl)- pipérazinyle, morpholinyle, thiomorpholinyle, 1-oxothiomorpholinyle et 1,1-dioxo- thiomorpholinyle ;
    R4b est hydrogène, C1-4alkyle ou C1-4alkyle substitué par un substituant choisi dans le groupe constitué d'amino, mono- ou di(C1- 4alkyl)amino, pyrrolidinyle, pipéridinyle, homopipéridinyle, pipérazinyle, 4-(C1-4alkyl)- pipérazinyle, morpholinyle, thiomorpholinyle, 1-oxothiomorpholinyle et 1,1-dioxo- thiomorpholinyle ;
    aryle est phényle éventuellement substitué par un ou plusieurs substituants choisis chacun individuellement dans le groupe constitué de C1-6alkyle, C1-4alcoxy, halogéno, hydroxy, amino, trifluorométhyle, cyano, nitro, hydroxyC1-6alkyle, cyanoC1-6alkyle, mono- ou di(C1-6alkyl)amino, aminoC1-4alkyle, mono- ou di(C1-4alkyl)aminoC1-4alkyle ;
    Het1 est un système de cycle à 5 chaînons dans lequel un, deux, trois ou quatre membres du cycle sont des hétéroatomes choisis chacun individuellement et indépendamment dans le groupe constitué d'azote, d'oxygène et de soufre, et où les membres de cycle restants sont des atomes de carbone ; et, lorsque c'est possible, tout azote membre du cycle peut éventuellement être substitué par C1- 4alkyle ; tout atome de carbone du cycle peut, chacun individuellement et indépendamment, éventuellement être substitué par un substituant choisi dans le groupe constitué de C1-4alkyle, C2-6alcényle, C3-7cycloalkyle, hydroxy, C1-4alcoxy, halogéno, amino, cyano, trifluorométhyle, hydroxyC1-4alkyle, cyanoC1- 4alkyle, mono- ou di(C1-4alkyl)amino, aminoC1- 4alkyle, mono- ou di(C1-4alkyl)aminoC1-4alkyle, arylC1-4alkyle, aminoC2-6alcényle, mono- ou di (C1-4alkyl) aminoC2-6alcényle, furanyle, thiényle, pyrrolyle, oxazolyle, thiazolyle, imidazolyle, isoxazolyle, isothiazolyle, pyrazolyle, oxadiazolyle, thiadiazolyle, triazolyle, tétrazolyle, aryle, hydroxycarbonyle, aminocarbonyle, C1- 4alkyloxycarbonyle, mono- ou di(C1- 4alkyl)aminocarbonyle, C1-4alkylcarbonyle, oxo, thio ; et où l'un quelconque des motifs furanyle, thiényle, pyrrolyle, oxazolyle, thiazolyle, imidazolyle, isoxazolyle, isothiazolyle, pyrazolyle, oxadiazolyle, thiadiazolyle et triazolyle précédents peut éventuellement être substitué par C1-4alkyle ;
    Het2 est pyridyle, pyrimidinyle, pyrazinyle, pyridazinyle ou triazinyle, où tout atome de carbone du cycle de chacun desdits cycles aromatiques azotés à 6 chaînons peut éventuellement être substitué par un substituant choisi dans le groupe constitué de C1-4alkyle ;
    à condition que le composé de formule (I) soit différent de
    2,5-dihydro-1-(4-nitrophényl)-2-oxo-1H-pyrido[3,2-b]indole-3-carbonitrile, et
    2,5-dihydro-5-méthyl-1-(4-nitrophényl)-2-oxo-1H-pyrido[3,2-b]indole-3-carbonitrile.
  2. Composé selon la revendication 1, caractérisé en ce que n est 1, R3 est nitro, R1 est cyano, C1-4alkyloxycarbonyle ou C1-4alkylaminocarbonyle ; et R2 est hydrogène ou C1-6alkyle.
  3. Composé selon la revendication 1 ou 2, caractérisé en ce que
    n est 1 ou 2 ;
    R3 est nitro, cyano, amino, halogéno, hydroxy, C1- 4alkyloxy, hydroxycarbonyle, aminocarbonyle, aminothiocarbonyle, C1-4alkyloxycarbonyle, C1- 4alkylcarbonyle, mono- ou di(C1- 4alkyl)méthanimidamidyle, N-hydroxy- méthanimidamidyle ou Het1.
  4. Composé selon l'une quelconque des revendications 1 à 3, caractérisé en ce que
    R1 est hydrogène, cyano, halogéno, aminocarbonyle, hydroxycarbonyle, C1-4alkyloxycarbonyle, arylaminocarbonyle, N-hydroxy- méthanimidamidyle, mono- ou di (C1-4alkyl)- méthanimidamidyle, Het1 ou Het2; et
    aryle est phényle éventuellement substitué par un ou plusieurs substituants choisis chacun individuellement dans le groupe constitué de C1-6alkyle, C1-4alcoxy, cyano, nitro ; et
    Het1 est un système de cycle à 5 chaînons dans lequel un, deux, trois ou quatre membres du cycle sont des hétéroatomes choisis chacun individuellement et indépendamment dans le groupe constitué d'azote, d'oxygène et de soufre, et où les membres de cycle restants sont des atomes de carbone; et, lorsque c'est possible, tout azote membre du cycle peut éventuellement être substitué par C1- 4alkyle; tout atome de carbone du cycle peut, chacun individuellement et indépendamment, éventuellement être substitué par un substituant choisi dans le groupe constitué de C1-4alkyle, C3-7cycloalkyle, halogéno, cyano, trifluorométhyle, cyanoC1-4alkyle, mono- ou di(C1-4alkyl)amino, mono- ou di(C1- 4alkyl)aminoC2-6alcényle, isoxazolyle, aryle, hydroxycarbonyle, C1-4alkyloxycarbonyle, oxo, thio ; et où l'isoxazolyle précédent peut éventuellement être substitué par C1-4alkyle; et
    Het2 est pyridyle.
  5. Composé selon l'une quelconque des revendications 1 à 4, caractérisé en ce que
    R2 est hydrogène, C1-10alkyle, C2-10alcényle, C3- 7cycloalkyle ou C1-10alkyle substitué par un substituant choisi dans le groupe constitué de cyano, NR4aR4b, pyrrolidinyle, pipéridinyle, 4-(C1-4alkyl)-pipérazinyle, morpholinyle, aryle, imidazolyle, pyridyle, hydroxycarbonyle, N(R4aR4b)carbonyle, C1- 4alkyloxycarbonyle ou 4-(C1-4alkyl) -pipérazin- 1-ylcarbonyle ; et
    R4a est C1-4alkyle; et
    R4b est C1-4alkyle ou morpholinyle substitué par C1-4alkyle.
  6. Composé selon l'une quelconque des revendications 1 à 5, caractérisé en ce que
    R2 est hydrogène, C1-10alkyle, C2-10alcényle, C3- 7cycloalkyle ou C1-10alkyle substitué par un substituant choisi dans le groupe constitué de cyano, NR4aR4b, pyrrolidinyle, pipéridinyle, 4-(C1-4alkyl)-pipérazinyle, morpholinyle, aryle, imidazolyle, pyridyle, hydroxycarbonyle, N(R4aR4b)carbonyle, C1- 4alkyloxycarbonyle ou 4-(C1-4alkyl)-pipérazin- 1-ylcarbonyle ; et
    aryle est phényle éventuellement substitué par un ou plusieurs substituants choisis chacun individuellement dans le groupe constitué de C1-6alkyle, C1-4alcoxy, cyano, nitro.
  7. Composé selon l'une quelconque des revendications 1 à 6, caractérisé en ce que
    R2 est hydrogène, C1-10alkyle, C2-10alcényle, C3- 7cycloalkyle ou C1-10alkyle substitué par un substituant choisi dans le groupe constitué de cyano, NR4aR4b, pyrrolidinyle, pipéridinyle, 4-(C1-4alkyl)-pipérazinyle, morpholinyle, aryle, imidazolyle, pyridyle, hydroxycarbonyle, N(R4aR4b)carbonyle, C1- 4alkyloxycarbonyle ou 4-(C1-4alkyl)-pipérazin- 1-ylcarbonyle ; et
    aryle est phényle éventuellement substitué par un ou plusieurs substituants choisis chacun individuellement dans le groupe constitué de C1-6alkyle, C1-4alcoxy, cyano, nitro ; et
    R4a est C1-4alkyle ; et
    R4b est C1-4alkyle ou morpholinyle substitué par C1-4alkyle.
  8. Composé selon l'une quelconque des revendications 1 à 7, caractérisé en ce que
    R3 est nitro, cyano, amino, halogéno, hydroxy, C1- 4alkyloxy, hydroxycarbonyle, aminocarbonyle, aminothiocarbonyle, C1-4alkyloxycarbonyle, C1- 4alkylcarbonyle, mono- ou di(C1- 4alkyl)méthanimidamidyle, N-hydroxy- méthanimidamidyle ou Het1 ; et
    Het1 est un système de cycle à 5 chaînons dans lequel un, deux, trois ou quatre membres du cycle sont des hétéroatomes choisis chacun individuellement et indépendamment dans le groupe constitué d'azote, d'oxygène et de soufre, et où les membres de cycle restants sont des atomes de carbone; et, lorsque c'est possible, tout azote membre du cycle peut éventuellement être substitué par C1- 4alkyle; tout atome de carbone du cycle peut, chacun individuellement et indépendamment, éventuellement être substitué par un substituant choisi dans le groupe constitué de C1-4alkyle, C3-7cycloalkyle, halogéno, cyano, trifluorométhyle, cyanoC1-4alkyle, mono- ou di(C1-4alkyl)amino, mono- ou di(C1- 4alkyl)aminoC2-6alcényle, isoxazolyle, aryle, hydroxycarbonyle, C1-4alkyloxycarbonyle, oxo, thio ; et où l'isoxazolyle précédent peut éventuellement être substitué par C1-4alkyle.
  9. Composé selon l'une quelconque des revendications 1 à 8, caractérisé en ce que
    n est 1 ou 2, plus particulièrement en ce que n est 1 ; et
    R1 est hydrogène, cyano, halogéno, aminocarbonyle, hydroxycarbonyle, C1-4alkyloxycarbonyle, arylaminocarbonyle, N-hydroxy- méthanimidamidyle, mono- ou di(C1-4alkyl)- méthanimidamidyle, Het1 ou Het2; et
    R2 est hydrogène, C1-10alkyle, C2-10alcényle, C3- 7cycloalkyle ou C1-10alkyle substitué par un substituant choisi dans le groupe constitué de cyano, NR4aR4b, pyrrolidinyle, pipéridinyle, 4-(C1-4alkyl)-pipérazinyle, morpholinyle, aryle, imidazolyle, pyridyle, hydroxycarbonyle, N(R4aR4b)carbonyle, C1- 4alkyloxycarbonyle ou 4-(C1-4alkyl)-pipérazin- 1-ylcarbonyle ; et
    R3 est nitro, cyano, amino, halogéno, hydroxy, C1- 4alkyloxy, hydroxycarbonyle, aminocarbonyle, aminothiocarbonyle, C1-4alkyloxycarbonyle, C1- 4alkylcarbonyle, mono- ou di(C1- 4alkyl)méthanimidamidyle, N-hydroxy- méthanimidamidyle ou Het1.
  10. Composé selon l'une quelconque des revendications 1 à 9, caractérisé en ce que le composé a la formule (II).
    Figure imgb0154
  11. Composé selon l'une quelconque des revendications 1 à 10, caractérisé en ce que R3 est nitro.
  12. Composé selon l'une quelconque des revendications 1 à 11, caractérisé en ce que R1 est cyano.
  13. Composé selon l'une quelconque des revendications 1 à 12, caractérisé en ce que R1 est C1-4alkyloxycarbonyle ou C1-4alkylaminocarbonyle.
  14. Composé selon l'une quelconque des revendications 1 à 13, caractérisé en ce que R2 est C2-6alkyle.
  15. Composé selon l'une quelconque des revendications 1 à 14, caractérisé en ce que
    n est 1,
    R1 est cyano, halogéno ou oxadiazolyle éventuellement substitué par un substituant choisi dans le groupe constitué de C1-4alkyle, C2-6alcényle, C3-7cycloalkyle, hydroxy, C1- 4alcoxy, amino, cyano, trifluorométhyle, hydroxyC1-4alkyle, cyanoC1-4alkyle, mono- ou di(C1-4alkyl) amino, aminoC1-4alkyle, mono- ou di(C1-4alkyl) aminoC1-4alkyle, arylC1-4alkyle, aminoC2-6alcényle, mono- ou di(C1- 4alkyl)aminoC2-6alcényle, furanyle, thiényle, pyrrolyle, oxazolyle, thiazolyle, imidazolyle, isoxazolyle, isothiazolyle, pyrazolyle, oxadiazolyle, thiadiazolyle, triazolyle, tétrazolyle, aryle, hydroxycarbonyle, aminocarbonyle, C1- 4alkyloxycarbonyle, mono- ou di(C1- 4alkyl)aminocarbonyle, C1-4alkylcarbonyle, oxo, thio ; et où l'un quelconque des motifs furanyle, thiényle, pyrrolyle, oxazolyle, thiazolyle, imidazolyle, isoxazolyle, isothiazolyle, pyrazolyle, oxadiazolyle, thiadiazolyle et triazolyle précédents peut éventuellement être substitué par C1-4alkyle;
    R2 est C1-6alkyle, hydrogène, C2-6alcényle,
    R3 est nitro, C1-6alkyle éventuellement substitué par pipéridinyle, pyrrolidinyle, N(R4aR4b), morpholinyle, pyridyle, cyano, 4-(C1-4alkyl)- pipérazin-1-yle.
  16. Composé selon la revendication 1, caractérisé en ce que le composé est
    le 5-isobutyl-1-(4-nitro-phényl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile ;
    le 5-allyl-1-(4-nitro-phényl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile ;
    le 5-butyl-1-(4-nitro-phényl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile ;
    le 5-éthyl-1-(4-nitro-phényl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile ;
    le 5-(2-morpholin-4-yl-éthyl)-1-(4-nitro-phényl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile ;
    le 5-méthyl-1-(4-nitro-phényl)-1,5-dihydro-pyrido[3,2-b]indol-2-one ;
    le 5-but-3-ényl-1-(4-nitro-phényl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
    le 1-(4-nitro-phényl)-2-oxo-5-(2-pyrrolidin-1-yl-éthyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile ;
    le 1-(4-nitro-phényl)-2-oxo-5-(2-pipéridin-1-yl-éthyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile ;
    le 5-(3-diméthylamino-propyl)-1-(4-nitro-phényl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile ;
    la 3-bromo-5-méthyl-1-(4-nitro-phényl)-1,5-dihydro-pyrido[3,2-b]indol-3-one
    le 5-méthyl-1-(3-nitro-phényl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile ;
    le 1-(4-nitro-phényl)-2-oxo-5-(3-pipéridin-1-yl-propyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile ;
    le 5-(4-morpholin-4-yl-butyl)-1-(4-nitro-phényl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile ;
    le 1-(4-nitro-phényl)-2-oxo-5-(4-pyrrolidin-1-yl-butyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile ;
    le 5-[3-(4-méthyl-pipérazin-1-yl)-propyl]-1-(4-nitro-phényl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
    le 5-cyanométhyl-1-(4-nitro-phényl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile ;
    le 5-(3-morpholin-4-yl-propyl)-1-(4-nitro-phényl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile ;
    le 1-(4-nitro-phényl)-2-oxo-5-(4-pipéridin-1-yl-butyl)-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile ;
    le 5-(4-diméthylamino-butyl)-1-(4-nitro-phényl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile ;
    le 1-(4-nitro-phényl)-2-oxo-5-pyridin-4-ylméthyl-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile ;
    le 3-(5-tert-butyl-[1,2,4]oxadiazol-3-yl)-5-méthyl-1-(4-nitro-phényl)-1,5-dihydro-pyrido[3,2-b]indol-2-one;
    la 5-méthyl-1-(4-nitro-phényl)-3-(5-trifluorométhyl-[1,2,4]oxadiazol-3-yl)-1,5-dihydro-pyrido[3,2-b]indol-2-one ; ou un N-oxyde, un sel ou un stéréoisomère de ceux-ci.
  17. Composé de formule (I)
    Figure imgb0155
     son N-oxyde, son sel, sa forme stéréoisomère, son mélange racémique,
    dans laquelle
    n est 1, 2 ou 3 ;
    R1 est hydrogène, cyano, halogéno, aminocarbonyle, hydroxycarbonyle, C1-4alkyloxycarbonyle, C1- 4alkylcarbonyle, mono- ou di(C1- 4alkyl)aminocarbonyle, arylaminocarbonyle, N- (aryl)-N-(C1-4alkyl) aminocarbonyle, méthanimidamidyle, N-hydroxy- méthanimidamidyle, mono- ou di(C1- 4alkyl)méthanimidamidyle, Het1 ou Het2;
    R2 est hydrogène, C1-10alkyle, C2-10alcényle, C3- 7cycloalkyle, où lesdits C1-10alkyle, C2- 10alcényle et C3-7cycloalkyle, chacun individuellement et indépendamment, peuvent être éventuellement substitués par un substituant choisi dans le groupe constitué de cyano, NR4aR4b, pyrrolidinyle, pipéridinyle, homopipéridinyle, pipérazinyle, 4-(C1-4alkyl)- pipérazinyle, morpholinyle, thiomorpholinyle, 1-oxothiomorpholinyle, 1,1-dioxo- thiomorpholinyle, aryle, furanyle, thiényle, pyrrolyle, oxazolyle, thiazolyle, imidazolyle, isoxazolyle, isothiazolyle, pyrazolyle, oxadiazolyle, thiadiazolyle, triazolyle, tétrazolyle, pyridyle, pyrimidinyle, pyrazinyle, pyridazinyle, triazinyle, hydroxycarbonyle, C1- 4alkylcarbonyle, N(R4aR4b) carbonyle, C1- 4alkyloxycarbonyle, pyrrolidin-1-ylcarbonyle, pipéridin-1-ylcarbonyle, homopipéridin-1- ylcarbonyle, pipérazin-1-ylcarbonyle, 4-(C1- 4alkyl)-pipérazin-1-ylcarbonyle, morpholin-1- yl-carbonyle, thiomorpholin-1-ylcarbonyle, 1- oxothiomorpholin-1-ylcarbonyle et 1,1-dioxo- thiomorpholin-1-ylcarbonyle;
    R3 est nitro, cyano, amino, halogéno, hydroxy, C1- 4alkyloxy, hydroxycarbonyle, aminocarbonyle, C1-4alkyloxycarbonyle, mono- ou di(C1- 4alkyl)aminocarbonyle, C1-4alkylcarbonyle, méthanimidamidyle, mono- ou di(C1- 4alkyl)méthanimidamidyle, N-hydroxy- méthanimidamidyle ou Het1;
    R4a est hydrogène, C1-4alkyle ou C1-4alkyle substitué par un substituant choisi dans le groupe constitué d'amino, mono- ou di(C1- 4alkyl)amino, pyrrolidinyle, pipéridinyle, homopipéridinyle, pipérazinyle, 4-(C1-4alkyl)- pipérazinyle, morpholinyle, thiomorpholinyle, 1-oxothiomorpholinyle et 1,1-dioxo- thiomorpholinyle;
    R4b est hydrogène, C1-4alkyle ou C1-4alkyle substitué par un substituant choisi dans le groupe constitué d'amino, mono- ou di(C1- 4alkyl)amino, pyrrolidinyle, pipéridinyle, homopipéridinyle, pipérazinyle, 4-(C1-4alkyl)- pipérazinyle, morpholinyle, thiomorpholinyle, 1-oxothiomorpholinyle et 1,1-dioxo- thiomorpholinyle ;
    aryle est phényle éventuellement substitué par un ou plusieurs substituants choisis chacun individuellement dans le groupe constitué de C1-6alkyle, C1-4alcoxy, halogéno, hydroxy, amino, trifluorométhyle, cyano, nitro, hydroxyC1-6alkyle, cyanoC1-6alkyle, mono- ou di(C1-4alkyl) amino, aminoC1-4alkyle, mono- ou di(C1-4alkyl)aminoC1-4alkyle;
    Het1 est un système de cycle à 5 chaînons dans lequel un, deux, trois ou quatre membres du cycle sont des hétéroatomes choisis chacun individuellement et indépendamment dans le groupe constitué d'azote, d'oxygène et de soufre, et où les membres de cycle restants sont des atomes de carbone; et, lorsque c'est possible, tout azote membre du cycle peut éventuellement être substitué par C1- 4alkyle; tout atome de carbone du cycle peut, chacun individuellement et indépendamment, éventuellement être substitué par un substituant choisi dans le groupe constitué de C1-4alkyle, C2-6alcényle, C3-7cycloalkyle, hydroxy, C1-4alcoxy, halogéno, amino, cyano, trifluorométhyle, hydroxyC1-4alkyle, cyanoC1- 4alkyle, mono- ou di(C1-4alkyl)amino, aminoC1- 4alkyle, mono- ou di(C1-4alkyl)aminoC1-4alkyle, arylC1-4alkyle, aminoC2-6alcényle, mono- ou di (C1-4alkyl) aminoC2-6alcényle, furanyle, thiényle, pyrrolyle, oxazolyle, thiazolyle, imidazolyle, isoxazolyle, isothiazolyle, pyrazolyle, oxadiazolyle, thiadiazolyle, triazolyle, tétrazolyle, aryle, hydroxycarbonyle, aminocarbonyle, C1- 4alkyloxycarbonyle, mono- ou di(C1- 4alkyl)aminocarbonyle, C1-4alkylcarbonyle, oxo, thio ; et où l'un quelconque des motifs furanyle, thiényle, pyrrolyle, oxazolyle, thiazolyle, imidazolyle, isoxazolyle, isothiazolyle, pyrazolyle, oxadiazolyle, thiadiazolyle et triazolyle précédents peut éventuellement être substitué par C1-4alkyle;
    Het2 est pyridyle, pyrimidinyle, pyrazinyle, pyridazinyle ou triazolyle, où tout atome de carbone du cycle de chacun desdits cycles aromatiques azotés à 6 chaînons peut éventuellement être substitué par un substituant choisi dans le groupe constitué de C1-4alkyle ;
    destiné à être utilisé comme médicament.
  18. Composé tel que décrit dans la revendication 17, destiné à être utilisé comme médicament, caractérisé en ce que
    R1 est cyano, C1-4alkyloxycarbonyle ou C1- 4alkylaminocarbonyle;
    R2 est hydrogène ou C1-6alkyle.
  19. Composé tel que décrit dans la revendication 17 ou 18, destiné à être utilisé comme médicament, caractérisé en ce que le composé a la formule (II)
    Figure imgb0156
     destiné à être utilisé comme médicament.
  20. Composé tel que décrit dans l'une quelconque des revendications 17 à 19, destiné à être utilisé comme médicament, caractérisé en ce que R1 est cyano, méthyloxycarbonyle, méthylaminocarbonyle, éthylaminocarbonyle, éthyloxycarbonyle.
  21. Composé tel que décrit dans l'une quelconque des revendications 17 à 20, destiné à être utilisé comme médicament, caractérisé en ce que R2 est hydrogène ou méthyle.
  22. Composé tel que décrit dans l'une quelconque des revendications 17 à 21, destiné à être utilisé comme médicament, caractérisé en ce que R1 est cyano et R2 est hydrogène ou méthyle.
  23. Utilisation d'un composé de formule (I) tel que défini dans l'une quelconque des revendications 17 à 22, pour la fabrication d'un médicament destiné à prévenir, traiter ou combattre une infection ou maladie associée à l'infection par le virus VIH.
  24. Utilisation d'un composé de formule (I) tel que défini dans l'une quelconque des revendications 17 à 22, pour la fabrication d'un médicament destiné à inhiber la réplication du virus VIH.
  25. Utilisation d'un composé de formule (I) selon la revendication 23 ou 24, caractérisée en ce que la transcriptase inverse du virus VIH est mutante.
  26. Composition pharmaceutique, comprenant une quantité efficace d'au moins un composé de formule (I) tel que défini dans l'une quelconque des revendications 1 à 17, autre que le 1-p-nitrophényl-3-cyano-1,2-dihydropyrido[3,2-b]indol-2-one, le 2,5-dihydro-1-(4-nitrophényl)-2-oxo-1H-pyrido[3,2-b]indole-3-carbonitrile, et un excipient pharmaceutiquement tolérable.
  27. Produit contenant au moins un composé de formule (I) tel que défini dans l'une quelconque des revendications 1 à 17 et un agent antirétroviral en tant que préparation combinée destinée à une utilisation simultanée, séparée ou séquentielle dans une thérapie antirétrovirale.
EP03811395A 2002-11-15 2003-11-14 Indolepyridinium substitue utilise comme composes anti-infection Expired - Lifetime EP1594870B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP03811395A EP1594870B1 (fr) 2002-11-15 2003-11-14 Indolepyridinium substitue utilise comme composes anti-infection

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP02079783 2002-11-15
EP02079783 2002-11-15
US43495002P 2002-12-20 2002-12-20
US434950P 2002-12-20
EP03811395A EP1594870B1 (fr) 2002-11-15 2003-11-14 Indolepyridinium substitue utilise comme composes anti-infection
PCT/EP2003/050837 WO2004046143A1 (fr) 2002-11-15 2003-11-14 Indolepyridinium substitue utilise comme composes anti-infection

Publications (2)

Publication Number Publication Date
EP1594870A1 EP1594870A1 (fr) 2005-11-16
EP1594870B1 true EP1594870B1 (fr) 2011-05-11

Family

ID=32327852

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03811395A Expired - Lifetime EP1594870B1 (fr) 2002-11-15 2003-11-14 Indolepyridinium substitue utilise comme composes anti-infection

Country Status (16)

Country Link
US (2) US7608726B2 (fr)
EP (1) EP1594870B1 (fr)
JP (1) JP2006508145A (fr)
KR (1) KR20050084621A (fr)
CN (1) CN100457754C (fr)
AP (1) AP1927A (fr)
AU (1) AU2003296760B2 (fr)
BR (1) BR0316209A (fr)
CA (1) CA2506316A1 (fr)
EA (1) EA009871B1 (fr)
HR (1) HRP20050543A2 (fr)
MX (1) MXPA05005146A (fr)
NO (1) NO20052884L (fr)
NZ (1) NZ540321A (fr)
PL (1) PL376683A1 (fr)
WO (1) WO2004046143A1 (fr)

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY169670A (en) 2003-09-03 2019-05-08 Tibotec Pharm Ltd Combinations of a pyrimidine containing nnrti with rt inhibitors
KR20070011588A (ko) * 2004-05-17 2007-01-24 티보텍 파마슈티칼즈 리미티드 치환된 1-페닐-1,5-디히드로-피리도-[3,2-ｂ]인돌-2-온 및다른 ｈｉｖ 억제제의 배합물
CN1953978B (zh) * 2004-05-17 2010-09-29 泰博特克药品有限公司 作为抗病毒剂的5-取代的1-苯基-1,5-二氢-吡啶并[3,2-b]吲哚-2-酮及其类似物
ATE481403T1 (de) * 2004-05-17 2010-10-15 Tibotec Pharm Ltd Substituierte 1-phenyl-1,5-dihydro-pyridoä3,2- büindol-2-on-derivate verwendbar als pharmazeutische antiinfektiva
EP1758911A1 (fr) * 2004-05-17 2007-03-07 Tibotec Pharmaceuticals Ltd. 1-heterocyclyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones
MXPA06013315A (es) 2004-05-17 2007-02-02 Tibotec Pharm Ltd 1,5-dihidro-pirido[3,2-b]indol-2-onas 4-sustituidas.
AU2005288864B2 (en) 2004-09-30 2012-08-23 Janssen Sciences Ireland Uc HIV inhibiting 5-heterocyclyl pyrimidines
CN101027288B (zh) 2004-09-30 2013-04-17 泰博特克药品有限公司 抑制hiv的5-取代嘧啶
TW200637862A (en) * 2005-01-10 2006-11-01 Tibotec Pharm Ltd 1,5,6-substituted-2-oxo-3-cyano-1,6a-diaza-tetrahydro-fluoranthenes
EP1853720A1 (fr) * 2005-02-04 2007-11-14 Tibotec Pharmaceuticals Ltd. Procede d'identification d'inhibiteurs competitifs de transcriptase inverse du vih
US20090012046A1 (en) * 2006-02-03 2009-01-08 Dirk Edward Desire Jochmans Methods of Treating Mutated Hiv
EP2004632B1 (fr) 2006-03-30 2014-03-12 Janssen R&D Ireland Pyrimidines à substitution 5-amido inhibant le vih
WO2008037783A1 (fr) * 2006-09-29 2008-04-03 Tibotec Pharmaceuticals Ltd. Processus de préparation de 2-oxo-2,5-dihydro-1h-pyrido[3,2-b]indole-3-carbonitriles
BRPI0720858B8 (pt) 2006-12-29 2021-05-25 Janssen R & D Ireland pirimidinas 6-substituídas inibidoras de hiv e composição farmacêutica que as compreende
AU2007341228B2 (en) 2006-12-29 2013-04-18 Janssen Sciences Ireland Uc HIV inhibiting 5,6-substituted pyrimidines
AR065720A1 (es) 2007-03-14 2009-06-24 Tibotec Pharm Ltd Polvos para reconstitucion que comprenden rilpivirina dispersos en ciertos polimeros. uso. proceso.
US8426434B2 (en) 2007-07-12 2013-04-23 Tibotec Pharmaceuticals Ltd. Crystalline form of 4-[[4-[[4-(2-Cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]amino]benzonitrile
WO2010085582A1 (fr) * 2009-01-23 2010-07-29 Bristol-Myers Squibb Company Dérivés d'oxadiazole substitués comme agonistes de s1p dans le traitement de maladies auto-immunes et inflammatoires
JP2012515789A (ja) 2009-01-23 2012-07-12 ブリストル−マイヤーズ スクイブ カンパニー スフィンゴシン−１−リン酸アゴニストとしてのピラゾール−１，２，４−オキサジアゾール誘導体
US8354398B2 (en) 2009-01-23 2013-01-15 Bristol-Myers Squibb Company Substituted isoxazole compounds
KR20120034592A (ko) 2009-04-09 2012-04-12 베링거 인겔하임 인터내셔날 게엠베하 Ｈｉｖ 복제의 저해제
EP2386541A1 (fr) * 2010-05-14 2011-11-16 Affectis Pharmaceuticals AG Nouveaux procédés de préparation d'antagonistes de P2X7R
CN103025706A (zh) 2010-07-28 2013-04-03 住友化学株式会社 羧酸酰胺的制造方法
UA115576C2 (uk) 2012-12-06 2017-11-27 Байєр Фарма Акцієнгезелльшафт Похідні бензимідазолу як антагоністи ер4
UY36999A (es) * 2015-12-02 2017-06-30 Syngenta Participations Ag Derivados de aryl oxadiazol fungicidas
US11066396B2 (en) * 2016-06-23 2021-07-20 Merck Sharp & Dohme Corp. 3-aryl- heteroaryl substituted 5-trifluoromethyl oxadiazoles as histonedeacetylase 6 (HDAC6) inhibitors
KR200486209Y1 (ko) 2016-07-05 2018-04-16 박우 편육 가공기구
CN108299428B (zh) * 2018-04-04 2019-09-27 山东大学 8-胺基-7-甲酸甲酯-吡嗪骈吡啶酮衍生物及其制备方法与应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002059123A2 (fr) * 2000-12-18 2002-08-01 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Composes benzoylalkylindolepyridinium et compositions pharmaceutiques comprenant ces composes
AU2002246658A1 (en) 2000-12-18 2002-07-24 Makarov, Vadim Benzoylalkylindolepyridinium compounds and pharmaceutical compositions comprising such compounds

Also Published As

Publication number Publication date
CA2506316A1 (fr) 2004-06-03
BR0316209A (pt) 2005-09-27
HRP20050543A2 (en) 2006-09-30
AP1927A (en) 2008-12-10
CN1738816A (zh) 2006-02-22
JP2006508145A (ja) 2006-03-09
AP2005003334A0 (en) 2005-06-30
US20060173000A1 (en) 2006-08-03
CN100457754C (zh) 2009-02-04
EA009871B1 (ru) 2008-04-28
NO20052884D0 (no) 2005-06-14
PL376683A1 (pl) 2006-01-09
MXPA05005146A (es) 2005-07-22
AU2003296760A1 (en) 2004-06-15
WO2004046143A1 (fr) 2004-06-03
NZ540321A (en) 2007-09-28
NO20052884L (no) 2005-08-15
US7608726B2 (en) 2009-10-27
US20100048563A1 (en) 2010-02-25
EA200500822A1 (ru) 2005-12-29
AU2003296760B2 (en) 2009-11-19
EP1594870A1 (fr) 2005-11-16
KR20050084621A (ko) 2005-08-26

Similar Documents

Publication Publication Date Title
EP1594870B1 (fr) Indolepyridinium substitue utilise comme composes anti-infection
US20070249655A1 (en) 4-Substituted-1,5-Dihydro-Pyrido[3,2-B]Indol-2-Ones
US7622582B2 (en) Derivatives of 1-phenyl-benzofuro[3,2]pyridin-2(1H)-one
EP1751156B1 (fr) 1-phényl-1,5-dihydro-pyrido[3,2-b]indol-2-ones substitués en tant qu' agents pharmaceutiques anti-infectieux
US7615639B2 (en) 1-pyridyl-benzofuro[3,2-b]pyridin-2(1H)-ones
JP2006516606A (ja) Ｈｉｖインテグラーゼインヒビター、医薬組成物、およびそれらの使用
CZ20033290A3 (cs) Širokospektré @@amino@benzoxazolové sulfonamidové inhibitory HIV proteasy
RU2362776C2 (ru) 5-ЗАМЕЩЕННЫЕ 1-ФЕНИЛ-1,5-ДИГИДРОПИРИДО[3,2-b]ИНДОЛ-2-ОНЫ И АНАЛОГИ КАК ПРОТИВОВИРУСНЫЕ ПРЕПАРАТЫ
ZA200503835B (en) Substituted indolepyridinium as anti-infective compounds
UA81268C2 (en) Substituted indolepyridinium as anti-infective compounds

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20050615

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1085472

Country of ref document: HK

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: TIBOTEC PHARMACEUTICALS LTD.

17Q First examination report despatched

Effective date: 20090115

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: TIBOTEC PHARMACEUTICALS

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 31/12 20060101ALI20101018BHEP

Ipc: A61K 31/437 20060101AFI20101018BHEP

Ipc: C07D 471/04 20060101ALI20101018BHEP

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 60337103

Country of ref document: DE

Effective date: 20110622

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

LTIE Lt: invalidation of european patent or patent extension

Effective date: 20110511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110511

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110912

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110511

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110822

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110812

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110511

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110511

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110511

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110511

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20111114

Year of fee payment: 9

Ref country code: FR

Payment date: 20111118

Year of fee payment: 9

Ref country code: LU

Payment date: 20111128

Year of fee payment: 9

Ref country code: IE

Payment date: 20111110

Year of fee payment: 9

Ref country code: MC

Payment date: 20111026

Year of fee payment: 9

Ref country code: NL

Payment date: 20111117

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110511

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110511

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110511

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20111114

Year of fee payment: 9

26N No opposition filed

Effective date: 20120214

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110511

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 60337103

Country of ref document: DE

Effective date: 20120214

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1085472

Country of ref document: HK

BERE Be: lapsed

Owner name: TIBOTEC PHARMACEUTICALS

Effective date: 20121130

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20130601

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110811

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20121114

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121130

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121130

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20130731

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121130

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130601

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 60337103

Country of ref document: DE

Effective date: 20130601

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110511

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130601

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121114

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121114

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121114